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Chemical Structure| 468075-00-5 Chemical Structure| 468075-00-5

Structure of 468075-00-5

Chemical Structure| 468075-00-5

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Product Details of [ 468075-00-5 ]

CAS No. :468075-00-5
Formula : C7H3BrClF3O
M.W : 275.45
SMILES Code : FC(F)(F)OC1=CC=C(Cl)C(Br)=C1
English Name :2-Bromo-1-chloro-4-(trifluoromethoxy)benzene
MDL No. :MFCD06797751
InChI Key :LTBFNTUNLKPFPI-UHFFFAOYSA-N
Pubchem ID :2761405

Safety of [ 468075-00-5 ]

Computational Chemistry of [ 468075-00-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.14
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 45.84
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

9.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.52
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

4.37
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

5.26
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

3.59
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.73
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.9

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-4.51
Solubility 0.0085 mg/ml ; 0.0000309 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-4.28
Solubility 0.0145 mg/ml ; 0.0000525 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.49
Solubility 0.00889 mg/ml ; 0.0000323 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

Yes
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-4.88 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.8

Application In Synthesis of [ 468075-00-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 468075-00-5 ]

[ 468075-00-5 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 544-16-1 ]
  • [ 175278-17-8 ]
  • [ 468075-00-5 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; copper(II) chloride In acetonitrile at 20℃; for 1h; 25 DESCRIPTION 25.2-Bromo-1-chloro-4-(trifluoromethoxy)benzene To anhydrous copper [(II)] chloride (6.3g, 47mmol) in acetonitrile (lOOmL) was added tert-butyl nitrite (6.85mL, [58MMOL),] followed dropwise by a solution of [2-BROMO-4- (TRIFLUOROMETHOXY)] aniline (lOg, 39mmol) in acetonitrile [(15ML).] The solution was stirred at ambient temperature for 1 hour then poured into hydrochloric acid (250mL, 2M). The suspension formed was extracted with diethyl ether [(2X250ML)] and the extracts were dried [(MGS04).] Concentration yielded the title compound as an oil (7.82g, [28MMOL).] [ON] (360 MHz, [CDCL3)] : 7.51 [(1H,] d, J 3.2Hz), 7.48 [(1H,] d, J 8.8Hz), 7.15 [(1H,] dd, J 3.2 and 8.8Hz).
  • 2
  • [ 468075-00-5 ]
  • [ CAS Unavailable ]
  • [ 468075-01-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-bromo-1-chloro-4-(trifluoromethoxy)benzene; tri-n-butylvinyl tin In toluene for 0.75h; Stage #2: for 2h; Heating / reflux; 26 DESCRIPTION 26.1-Chloro-2-vinyl-4-(trifluoromethoxy)benzene (Description 25; [L.] [OG,] 3.6mmol) and tri-n-butylvinyl tin (1.21g, 3. [8MMOL)] were dissolved in toluene (20mL) and the solution was degassed for 45 minutes with nitrogen. Tetrakis (triphenylphosphine) palladium [(0)] (lOOmg) was then added and the solution heated at reflux for 2 hours. Once cooled, the solution was concentrated and the residue was purified by silica chromatography to give the title compound [(274MG,] [1.] [2MMOL).] [ON] (360 MHz, [CDCL3)] : 7.40-7. 36 (2H, m), 7.09-7. 01 (2H, m), 5.75 [(1H,] d, J 17.5Hz), 5.47 [(1H,] d, J [10.] 9Hz).
  • 3
  • [ 468075-00-5 ]
  • [ 139290-70-3 ]
  • [ 1241898-37-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-bromo-1-chloro-4-(trifluoromethoxy)benzene With tert.-butyl lithium In tetrahydrofuran; pentanes at -78℃; Stage #2: tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate In tetrahydrofuran; pentanes at 20℃; 16.1 INTERMEDIATE 16; [2-Cyclopropyl-5-(trifluoromethoxy)phenyl1(piperidin-4-yl)methanone hydrochloride; Step 1 : /erf -Butyl -4- { [2-chloro-5 -(trifluoromethoxy)phenyl] carbonyl 1 piperidine- 1 carboxvlate; To a -78 C solution of 2-bromo-l-chloro-4-(trifluoromethoxy)benzene (2.95 g, 10.7 mmol) in THF (55 mL) was slowly added teλt-butyllithium (1.7 M in pentanes, 12.6 niL, 21.4 mmol). After stirring at -78 C for a few minutes, a solution of tert-butyl-4- (methoxy(methyl)carbamoyl)piperidine-l-carboxylate (2.65 g, 9.73 mmol) in THF (2 mL) was added to the reaction mixture. At the end of the addition, the cold bath was removed and the reaction mixture was warmed to room temperature and stirred at this temperature for 1 h. The reaction mixture was re-cooled to -10 C and quenched with a saturated solution of ammonium chloride. The mixture was poured into a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by column chromatography through silica gel, eluting with 2% EtOAc in hexanes to 30% EtOAc in hexanes as a gradient, afforded the title compound.
With tert.-butyl lithium In tetrahydrofuran; pentane at -78 - 20℃; 16.1 Step 1: tert-Butyl-4-[2-chloro-5-(trifluoromethoxy)phenyl]carbonyl}piperidine-1-carboxylate To a -78° C. solution of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (2.95 g, 10.7 mmol) in THF (55 mL) was slowly added tert-butyllithium (1.7 M in pentanes, 12.6 mL, 21.4 mmol). After stirring at -78° C. for a few minutes, a solution of tert-butyl-4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (2.65 g, 9.73 mmol) in THF (2 mL) was added to the reaction mixture. At the end of the addition, the cold bath was removed and the reaction mixture was warmed to room temperature and stirred at this temperature for 1 h. The reaction mixture was re-cooled to -10° C. and quenched with a saturated solution of ammonium chloride. The mixture was poured into a separatory funnel and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by column chromatography through silica gel, eluting with 2% EtOAc in hexanes to 30% EtOAc in hexanes as a gradient, afforded the title compound.
  • 4
  • [ 468075-00-5 ]
  • [ 117-99-7 ]
  • [ 1331753-59-3 ]
YieldReaction ConditionsOperation in experiment
83% With 2-Picolinic acid; potassium phosphate; copper(l) iodide In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere;
  • 5
  • [ 468075-00-5 ]
  • [ 65374-14-3 ]
  • [ 1331753-49-1 ]
YieldReaction ConditionsOperation in experiment
91% With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; potassium carbonate In <i>tert</i>-butyl alcohol at 100℃; for 5h; Inert atmosphere;
  • 6
  • [ 468075-00-5 ]
  • [ 2835-77-0 ]
  • [ 1331753-45-7 ]
YieldReaction ConditionsOperation in experiment
88% With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; potassium carbonate In <i>tert</i>-butyl alcohol at 100℃; for 5h; Inert atmosphere;
  • 7
  • [ 468075-00-5 ]
  • [ 1241898-38-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tert.-butyl lithium / pentane; tetrahydrofuran / -78 - 20 °C 2: potassium phosphate; palladium diacetate / tricyclohexylphosphine / ethyl acetate; toluene; water; tetrahydrofuran / 24 h / 80 °C / Inert atmosphere
  • 8
  • [ 468075-00-5 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: tert.-butyl lithium / pentane; tetrahydrofuran / -78 - 20 °C 2: potassium phosphate; palladium diacetate / tricyclohexylphosphine / ethyl acetate; toluene; water; tetrahydrofuran / 24 h / 80 °C / Inert atmosphere 3: hydrogenchloride / 1,4-dioxane / 17 h / 20 °C
  • 10
  • [ 468075-00-5 ]
  • [ 1261483-31-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / 2585.81 Torr 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 2.25 h / 70 °C
Multi-step reaction with 2 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / ethanol / 16 h / 80 °C / 2585.81 Torr 2: lithium aluminium tetrahydride / 1 h / -40 °C
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / 16 h / 80 °C / 2585.81 Torr 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / -40 °C
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine / 16 h / 80 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / -40 °C
Multi-step reaction with 2 steps 1: triethylamine; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 16 h / 80 °C / 2585.81 Torr 2: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / -40 °C

  • 11
  • [ 468075-00-5 ]
  • [ 1433280-57-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / 2585.81 Torr 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 2.25 h / 70 °C 3: sulfuric acid; bromine; silver sulfate / water / 1 h / 20 °C
  • 12
  • [ 468075-00-5 ]
  • [ 1433280-56-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / 2585.81 Torr 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 2.25 h / 70 °C 3: sulfuric acid; bromine; silver sulfate / water / 1 h / 20 °C 4: tert.-butylhydroperoxide; potassium iodide / 48 h / Reflux
  • 13
  • [ 468075-00-5 ]
  • [ 1433280-58-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / 2585.81 Torr 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 2.25 h / 70 °C 3: sulfuric acid; bromine; silver sulfate / water / 1 h / 20 °C 4: tert.-butylhydroperoxide; potassium iodide / 48 h / Reflux 5: water; lithium hydroxide / methanol / 1 h / 60 °C 6: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C
  • 14
  • [ 468075-00-5 ]
  • [ 1433281-25-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine / 2585.81 Torr 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 2.25 h / 70 °C 3: sulfuric acid; bromine; silver sulfate / water / 1 h / 20 °C 4: tert.-butylhydroperoxide; potassium iodide / 48 h / Reflux 5: water; lithium hydroxide / methanol / 1 h / 60 °C 6: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C 7: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; toluene / 90 °C / Inert atmosphere; Sealed tube 8: hydrogenchloride / 1,4-dioxane / 1 h / 20 °C 9: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C
 

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